1. Field of the Invention
The present invention relates generally to decontamination of body tissues; and more particularly, but not by way of limitation, to external eradication of infectious pathogenic biological contaminants from blood or blood products prior to intravenous injection of such blood or blood products into a patient's body.
The present invention also relates to external eradication of infectious pathogenic biological contaminants from skin, cornea or semen prior to transplanting or introducing of such tissues into the recipient's body.
2. Brief Description of the Prior Art
Blood and blood products have been employed as therapeutic agents since the 19th century. It was, however, not until the early 1900's that transfusion of stored, anticoagulated blood became a reality when the first blood banks were organized in Chicago and New York City. Almost half a century later, in 1982, an estimated 9,349,700 units of whole blood were collected in the U.S. by 5400 blood banks and transfusion services.
One of the many problems that plagues the use of blood transfusions is the transmission of agents causing infectious disease. A number of these infectious agents are of serious clinical importance in that such agents are not only dangerous to the recipient patients, but can also pose a danger to physicians, and other hospital personnel, handling the blood and blood products.
Many efforts have been made to ensure that the blood to be transfused is free of pathogenic biological contaminants. So far, screening of blood donors and blood samples is the only effective method to ensure that the blood to be transfused is not contaminated with infectious agents. Unfortunately despite screening techniques, infections still occur following blood transfusions.
U.S. Pat. No. 3,041,242 describes a process for eradication of virus contained in dried plasma wherein the dried plasma is heated at an elevated temperature for a length of time followed by applying a gas lethal to microorganisms, under high vacuum conditions. However, the method is not applicable to the treatment of human whole blood; and the viability of the dried plasma would most likely be impaired during the process.
It has been documented that certain cells may be killed by irradiation after treating them with certain photochemicals. Attempts to use light absorbing dyes to trigger photoreactions in biological systems date back to early 1900's. For example, Jesionek and Tappenier in 1903 used white light to activate topically applied eosin on skin tumors. (Jesionek, A. and Tappenier, V.H. Aur Behandlung des Hautcarcinomes mit Fluoreszierenden Stoffen. Munch. Med Wochenschr. 41:2042-2044, 1930).
It has been known for over 30 years that hematoporphyrin derivatives accumulate in neoplastic, embryonic, and regenerating tissues. Thus, injected hematoporphyrin has been found to have localized and fluoresced in several types of tumor induced in mice (Figge, F.H.J., Weiland G.S., Mangiollo, L.0.: Cancer Detection and Therapy. Affinity of Neoplastic, Embryonic, and Traumatized Tissues for Porphyrins and Metalloporphyrins. Proc. Soc. Exp. Biol. Med. 64: 640-641, 1948)
The red fluorescence of hematoporphyrin has also been observed under ultraviolet light in various malignant tumors in patients who had been given large doses of crude mixtures of hematoporphyrin compounds (hereinafter referred to as Hpd) (Rasmussen-Taxdal, D.S., Ward, G.E., and Figge, F.H.J.: Fluorescence of Human Lymphatic and Cancer Tissues Following High Doses of Intravenous Hematoporphyrin. Cancer 8: 78-81, 1955). As a result, methods have been developed to capitalize on the unique property of Hpd as a tumor marker in the detection and localization of different forms of cancer (King, E.G., et al., Hematoporphyrin Derivative as a Tumor Marker in the Detection and Localization of Pulmonary Malignancy, In Recent Results in Cancer Research, Vol. 82, Springer-Verlag, Berlin-Heielberg, 1982, 90; Benson, R.D., et al, Detection and Localization of In Situ Carcinoma of the Bladder with Hematoporphyrin Derivative. Mayo Clinic Proc., 57:548, 1982).
Although the unique photodynamic properties of Hpd, as well as its affinity toward tumor cells, had long been known, it was more than half a century later that the potential of using Hpd to selectively destroy tumor cells was explored. The bulk of the research on the use of Hpd to selectively destroy tumor cells in human has been reviewed by Dougherty et al. (Dougherty, T. J. et al., Photoradiation Therapy-clinical and Drug Advances. In Porphyrin Photosensitization, D. Kessel and T.J. Dougherty, Eds., Plenum Press, N.Y. , PP. 3-13, 1983).
The emphasis on using Hpd as the photoactivating or light-activating compound in photoradiation of tumors is based on two important properties of Hpd. Firstly, as judged by fluorescence, Hpd is preferentially accumulated, and retained to a higher degree in malignant tumors than in surrounding normal tissue or benign tumors. Secondly, when properly photoactivated, Hpd causes the destruction of cells and tissue in which it resides. The generally accepted mechanism of cell kill by Hpd is that when activated by appropriate light, the Hpd can undergo an energy transfer process with oxygen to form a singlet oxygen, which subsequently oxidizes, hence kills the cells or tissues to which it has attached as a substrate. (Weishaupt, K.R., Gomer, C.J. and Dougherty, T.J. Identification of Singlet Oxygen as the Cytotoxic Agent in Photoinactivation of a Murine Tumor. Cancer Res. 36: 2326-2329, 1976).
Despite the enormous progress and research in the use of light-activated photosensitizer, such as Hpd, to pinpoint the location of malignant tumor cells and to eradicate them, relatively little work has been done to determine if such a photosensitizer will behave similarly toward virus, bacteria, fungi, protozoa, or other parasites.
U.S. Pat. No. 4,649,151 to Dougherty, et al., discloses the preparation, purification and utilization of tumor-selective, photosensitizing drugs (i.e. mixtures of porphyrins) in the localization and treatment of neoplastic tissue, such as tumors or cancers in patients and animals. A time delay of several hours to several days is required between injection of the drug and illumination in order for the drug to metabolically clear normal tissue and hence achieve the best therapeutic ratio of drug in tumor cells to drug in normal cells. One of the objects set forth in Dougherty, et al., is to provide a drug which is selective to certain pathogens within an animal or within blood, blood plasma or serum or fractions thereof and which permits photochemical destruction of the pathogens in vivo or in vitro. However, the reference contains no teaching or suggestion of the external purification of human tissues such as human blood, blood plasma, serum, semen, skin or cornea utilizing a mixture of porphyrins to eradicate infectious pathogens and to provide purified and sterilized human tissues such as human blood, blood plasma, human serum ,semen, skin or cornea which can be infused or introduced into a patient's body.
The Dougherty, et al., patent also fails to demonstrate the tolerance of either human blood, human blood plasma, or human serum outside the body toward the drug. Moreover, no evidence was provided to demonstrate that either human blood, human blood plasma, human serum, or other human tissues outside the body remains unchanged after the irradiation of such blood, blood plasma, serum, or other tissues containing the described drug. Similarly, neither the effective range of concentrations of the described drug nor the effective range of radiation is disclosed for its use outside an animal or human body.
U.S. Pat. No. 4,614,190 to Stanco, et al., discloses an arrangement for effecting photoirradiation of tumor and cancerous tissues in human or animal body. The patent discloses the method of pulsing the electromagnetic energy to activate, in situ, administered hematoporphrin derivative contained within the tissue in the body so that the surrounding flesh is not unduly affected.
This reference, however, neither teaches nor suggests the external purification of tissues such as blood, blood plasma, serum, semen, skin or cornea utilizing a mixture of porphyrins to eradicate infectious pathogens and to provide purified and sterilized tissues such as blood, blood plasma, serum, semen, skin or cornea which can be infused or introduced into the recipient's body.
The Stanco, et al., patent also fails to demonstrate the tolerance of either blood, blood plasma, serum, or other tissues outside the body toward the drug. Furthermore, no evidence was provided to demonstrate that either blood, blood plasma, serum, or other tissues outside the body remains undamaged after the irradiation of such blood, blood plasma, or serum, or other tissues containing the described drug. Similarly, neither the effective range of concentrations of the described drug nor the effective range of radiation is disclosed for its use outside an animal or human body.
Studies using fluorescence and laser techniques have suggested that hematoporphrin derivative (Hpd) would bind to parasites Plasmodium berqhei, P. vivax and P. falciparum. Moreover, whole animal studies utilizing a mixture of HPD and Chloroquine, an antimalarial drug, have reflected the reduction of the parasitemia in mice infected with Chloroquine resistant P. berghei. (F. Sogandares-Bernal, J.L. Matthews and M.M. Judy, HPD--Induced Reversal of Chloroquine Resistance to Malaria, a lecture presented at International Symposium on Malaria, held on June 1-5, 1986, at Instituo Oswaldo Cruz, Rio de Janeiro, Brazil,also in press, Mem. Inst. Oswald Cruz).
A few investigators have reported photoinactivating bacterial viruses and animal viruses using heterocyclic dyes (Yamamoto, N., Nitrogen Fixation by A Facultatibe Bacillus, J. Bacteriology, 75: 403, 1958; Hiatt, C.W., et al: Inactivation of Viruses by the Photodynamic Action of Toluidine Blue, J. Immunology, 84: 480-84, 1960). The plaque formation capability of Herpes simplex virus has also been reported to be hampered by the treatment of virus in culture with a combination of a hematoporphrin derivative and visible light. (Lewin, A.A., et al, Photodynamic Inactivation of Herpes simplex Virus by Hematoporphyrin Derivative and Light, Proc. Soc. Exp. Biol. Med. 163: 81-90, 1980).
Similarly, it has been reported that, in culture, the plaque formation by Herpes simplex virus type 1, Cytomeqalo-virus, or measles virus is reduced, by more than 99%, by the combination effect of Hpd and Rhodamine B dyelaser light, with an energy density of 20 J/cm.sup.2. On the other hand, the echovirus type 21, which lacks an envelope, is not affected under similar conditions (H. Skiles, M.M. Judy, and J.P. Newman, Photodynamic Inactivation of Viruses With Hematoporphyrin Derivatives, Abstract A 38, American Society for Microbiology page 7, 1985). The combined effect of light and Photofrin II.TM. on Herpes simolex virus type 1 grown in culture can be observed in a flow cell system made up of loops of transparent tubing attached to a glass slide, with a 1000W Xeon light equipped with a red filter serving as the light source. (F. Sogandares-Bernal, J. L. Matthews, H. Skiles, M.M. Judy, and J. Newman, Photoactivation of Herpes simplex virus by Photofrin II and Light in A Flow Cell System, 1987 ASM Annual Meeting, Atlanta, Ga., 1-6 March 1987).
Extracorporeal treatments of certain noninfectious cancers have been known for more than a decade. (H. Hyden, L.E. Gelin, S. Larsson, and A. Saarne, A New Specific Chemotherapy: A Pilot Study With An Extracorporeal Chamber. Rev. of Surgery (Philadelphia), 31: 305-320, 1974; H. Wolf, E. Langvad, and H. Hyden, The Clinical Course In Patients With Renal Carcinoma Subjected To Extracorporeal Immunoadsorption, British J. Urology, 53: 89-94, 1981). Recently, it was reported that the activity of a noninfectious cancer but nevertheless potentially deadly, cutaneous T-cell lymphoma, could be controlled by extra corporeal photochemotherapy. In the therapy, after patients were orally given 8-methoxypsoralen, blood was removed from the patient and the lymphocyte-enriched blood fraction was exposed to ultraviolet A. Subsequently, the damaged lymphocyte-enriched blood fraction was returned to the body of the patient. An immune reaction to the infused damage cells then restricted the activity of the abnormal cancer cells in the patient's body. (R. Edelson, et al., Treatment of Cutaneous T-Cell Lymphoma by Extracorporeal Photochemotherapy, New England J. Medicine, 316: 297-303, 1987).
The purpose of the extracorporeal photochemotherapy as reported by Edelson, et al., was not to damage as many cells as possible outside the patient's body. Rather, only a small fraction of the cells was damaged which was then reintroduced into the patient's body to serve as a "vaccine" for triggering an immune reaction in the body.
Despite the progress in photochemotherapy, no work, however, has been reported concerning the utility of such method to eradicate viruses present either in human whole blood or in other body tissues outside the body. Similarly, no one has reported the use of photoinactivation in a clinical setting to remove infectious agents, such as viruses, bacteria, fungi and protozoa, from human whole blood used for transfusion.
Viruses are, of course, completely different from malignant tumor cells. Unlike malignant tumor cells which are "uncontrollable" cells in human body, viruses are extremely tiny invaders. Tumor cells are visible under an ordinary microscope; in contrast, viruses are visible only with the aid of a high power electron microscope. Moreover, viruses lack most of the genetic materials present in malignant tumor cells. Indeed, a virus mainly consists of a very small number of genes, made up of either ribonuceleic acid (RNA) or deoxyribonucleic acid (DNA), encased, perhaps, in a protective coating of protein. Furthermore, diseases caused by viruses are contagious. In contrast, cancers composed of malignant tumor cells are not known to be contagious.
In view of the total difference between tumor cells and viruses, it is not surprising that clinically useful anticancer drugs are mostly ineffective for the treatment of viral diseases, and vice versa. Thus, as expected, 3-deoxy-3'-azidothymidine (AZT), currently one of the few experimental drugs used to control the proliferation of virus that causes the acquired immune deficiency syndrome (AIDS) is totally ineffective in preventing the proliferation of tumor cells. Likewise, Vincristine, a powerful anticancer drug, is ineffective in the treatment of viral diseases.
The word virus comes from the Latin for slimy liquid, stench, poison. The connotation is appropriate in view of the fact that untold number of varieties of viruses have long preyed on humans, animals and plants. Indeed, these infinitesimal, bizarre creatures may be mankind's deadliest enemy.
For examples, Hepatitis-B virus causes a hepatitis infection which may develop into cirrhosis in which the liver becomes a mass of fiber-like tissue. In hepatitis, liver function is impaired and, in some cases, the condition can be fatal. There are approximately 200,000 cases of reported hepatitis infections per year in this country. In addition, there may be as many as a few million carriers of hepatitis.
The human immunodeficiency virus (HIV), a retrovirus, is the cause of acquired immune deficiency syndrome (AIDS) which is invariably fatal. So far, the AIDS virus has infected more than a million people in this country alone. About one-third to one-half of the infected individuals will develop the disease. Worst yet, because the AIDS virus has a long and undeterminate period of incubation, a person can unknowingly carry and spread the deadly disease for years. The invariably fatal viral disease AIDS can be transmitted by the exchange of body tissues or body fluids such as blood, blood products, or semen. Indeed, hemophiliacs and others receiving blood transfusions account for about 3% of the reported AIDS cases in this country between 1981 and late 1986. Artificial insemenation, organ transplant, and transplant of skin, cornea and other tissues can also transmit this fatal viral disease.
In the presence of some co-factors, human T-cell leukemia virus, another retrovirus, can cause leukemia in human beings.
Smallpox, prior to its eradication, caused epidemics that devasted human populations in the 18th century. Polio virus is the cause of Poliomyelitis which infected some 400,000 Americans during its peak from 1943 to 1956, killing about half of them by paralysis and respiratory failure. Cytomegalovirus accounts for approximately half of all interstitial pneumonitis that occur in bone marrow transplant patients. It is a major cause of pneumonia in immunosuppressed patients, who often die from such illness. Furthermore, estimates vary, but from 20-30% of all persons in the U.S. receiving blood as a result of surgical procedures develop a post-transfusion syndrome believed to be caused blood infected with Cytomegalovirus.
Herpes simplex virus is the cause of oral, ocular, and genital sores for which there is no cure. Mumps virus is the cause of mumps, a disease which sometimes leads to aspermia due to complications.
Influenza virus that mutates every few years is the cause of Influenza for which there is no cure. Although most victims of influenza virus recover after a few days of suffering, the disease can sometimes be fatal.
Another harmful virus is adenovirus which is the cause of respiratory infections, such as sore throat. Rhinovirus is the cause of the common cold for which there is also no cure. There are approximately 200,000 cases of varicella (chicken pox) in the U.S.; whereas, zoster (shingles), a recurrent form of the disease affects about 2% of the population. Both of these diseases are caused by the same virus. The Epstein-Barr virus has been associated with infectious mononucleosis and hepatitis. The rate of infection with Epstein-Barr virus is approximately 150 cases per 100,000 population.
Viruses cause such a significant number of diseases in the population that these microorganisms sometimes threaten to reduce the number of people available to carry out the functions of the society. These viruses often attack the productive people in which society has made an investment.
People infected with virus may carry these agents or their particles in their blood. Likewise, people attacked by infectious diseases often carry pathogenic microorganisms or other contaminants in their blood. Consequently, blood donated or sold to blood banks may be contaminated with virus or other biological and pathogenic contaminants.
Most blood samples are now being tested for the presence of certain virus. These tests usually involve the determination of the presence of antibodies to various viruses or the viral antigen itself, such as HBsAg. Although most of the tests employed to test blood samples are generally quite accurate, they are not infallible. Also, due to cost considerations, not all blood is tested for the presence of pathogenic contaminants, including viruses. Most importantly, because antibodies do not form immediately after exposure to the virus, a newly infected person may unknowingly donate blood after becoming infected but before the antibody has a chance to manifest a positive test. It has also been documented that some people infected with certain viruses simply do not produce detectable antibodies against them.
A large number of diseases, some of which are either fatal or of serious clinical importance, can be transmitted by transfusion. Since pathogenic organisms are found in different fractions of whole blood, risks of post-transfusion diseases vary depending on the blood product or component used. In general, the risk for any disease is directly proportional to the volume of blood transfused and to the numbers of infectious organisms contained therein.
For example, post-transfusion hepatitis has long been a serious medical problem. In 1970, the National Research Council estimated that there were approximately 30,000 cases of clinical post-transfusion hepatitis per year with a mortality rate of about 10 percent. It was also estimated that there may be up to five times that many cases that are not clinically detectable. Other studies estimate the risk at about 7 cases per 1,000 units of blood transfused, with one-third of these being icteric. More recent studies, however, suggest a higher risk. The risk has been estimated as between 7 and 10 percent of all blood recipients. The risk of post-transfusion hepatitis is increased when blood from commercial donors is used. The introduction of universal hepatis B surface antigen (HBsAg) testing on all blood donated in this country has resulted in a reduction of type B related post-transfusion hepatitis. However, there continues to occur cases of type B post-transfusion hepatitis caused by blood showing negative HBsAg, hepatitis B surface antigen, as determined by the most sensitive tests currently available. Moreover, there is no reliable test for the detection of other forms of hepatitis, including hepatitis A, and non-A non-B. As discussed above, hepatitis infection not only is sometimes fatal by itself, the disease also may lead to fatal cancer of the liver, or may lead to additional complications in a patient already weakened by surgical or other trauma.
Another infectious disease most commonly transmitted by blood transfusion is caused by Cytomegalovirus which can precipitate the fatal interstitial pneumonitis. It has been shown that about 35 percent of patients who have been infused with fresh whole blood become infected with Cytomegalovirus.
Yet another infectious disease transmitted by blood transfusion is malaria. The incidence of transfusion-induced malaria has recently increased at an alarming rate. More than a million human beings infected with drug-resistant malaria are believed to die each year in Africa alone. There were more than 485,000 drug-resistant cases of malaria documented in Brazil during the first six months of 1986. In fact, many of the malaria infections in the world are now caused by parasites resistant to the most effective and least dangerous antimalarial agent, chloroquine. In erythrocytic phase, the malarial parasites reside exclusively in erythrocytes and are transmitted only with transfusion of products containing red blood cells. Without treatment, malaria can be fatal. These drug-resistant cases of malaria have proven most difficult to treat.
Still another hazard of blood transfusion is syphilis; although it does occur, the incidence is not very high. Nevertheless, syphilis is not a disease to be treated lightly. The disease can cause havoc to babies born of disease-carrying mothers. The disease can also cause cardiovascular and neurological complications. Chagas' disease, African trypanosomiasis, kala-azar, toxoplasmosis, and infections with microfilaria are other infectious agents that may be transmitted by transfusion of whole blood.
It is clear that despite screening techniques, infections with viruses and other biological pathogenic contaminants still occur following blood transfusions. In the setting of clinical medicine, the processing and handling of body fluids, such as blood, imposes a threat of a number of possible infections to physicians and other hospital workers, and patients. Currently, there is no effective procedure for decontaminating the infected body fluid, such as human whole blood or its formed elements.
It is, therefore, highly desirable to have a safe and economical method and apparatus that will eradicate pathogenic viruses, microorganisms, or parasites present in human whole blood or blood products before such products are infused into a recipient, hence, infecting the recipient with such disease producing agents. At the same time properly decontaminated blood will also spare the daily threat of infections to hospital personnel who must handle these body fluids. This need is even more acute in a blood bank where donor blood and blood products are stored and processed.
It is equally desirable to have a safe and economical method and apparatus that will eradicate pathogenic viruses, microorganisms, or parasites present in human or animal tissues, such as skin, cornea, and semen, before such tissues are introduced or transplanted into a recipient, hence, infecting the recipient with such diseases.
Since there is so far no cure for AIDS, it is also desirable to have a safe method and apparatus to reduce the viremia in AIDS patients to prolong the lives of such patients.
It is toward such goals that the present invention is directed.